The ketogenic diet is an established form of treatment for difficult to manage epilepsy.
Since ancient times, prolonged periods of fasting have been used to treat epilepsy, a seizure disorder. Early research reports proposed that the improvements in seizure control after 2-3 days of fasting were due to a change in metabolism, specifically the absence of carbohydrate food, which forced the body to utilize fat for energy.
Ketogenic diet (KD) is a term that refers to any diet therapy in which the composition of the diet would be expected to result in a state of ketosis. A KD is generally high-fat, low-carbohydrate, and moderate-protein. It forces the body to break down fat instead of glucose for energy. Both fat and glucose are able to provide ATP, the energy which drives cell metabolism. KD aims to mimic the metabolic state of fasting without actually inducing starvation.
KDs are precisely calculated to maintain adequate nutrient intake to prevent the malnutrition association with starvation to ensure continued healthy growth and development.
Use of KDs was common through the 1920s and 1930s. As pharmaceuticals grew in number, the KD fell out of favor. In recent decades, the KD has again risen in popularity, and with less-restrictive versions intended to enhance compliance, such as the Modified Atkins Diet (MAD) and low glycemic index treatment (LGIT).
Epilepsy is a chronic neurologic disorder that causes seizures. According to the Epilepsy Foundation, 65 million people have epilepsy worldwide, about 1/3 of which are considered to be uncontrolled and do not respond to standard medical treatment.
There are two broad categories of seizures – primary generalized and partial. Primary generalized seizures involve the entire brain and can be characterized as either tonic-clonic (convulsive, loss of consciousness) or absence seizures (loss of awareness, dazed). Partial seizures are either simple (maintain consciousness) or complex (loss of consciousness, followed by confusion).
Many seizures can be controlled by anti-epileptic drugs (AEDs), however others may requirement treatment via alternative treatment modalities, including diet therapy.
Although the mechanism(s) by which KD therapy controls seizures is not completely understood, the leading theories are either due to (1) alterations in energy metabolism including a decrease in glucose concentration with an increase in fatty acid oxidation and ketone production, or (2) alterations in neurotransmitter production, release, and uptake.
As dietary carbohydrates are reduced, blood glucose decreases and ketone levels rise. The KD reduces the supply of glucose which decreases the glycolysis pathway and, due to adequate energy (calorie) intake by way of fat consumption, prevents gluconeogenesis. This results in increased b-oxidation and a rise in ketone bodies which become the main energy source for brain cells.
As carbohydrate intake decreases and fat intake increases, blood sugar levels stabilize and ketone production from endogenous and dietary sources rise which offers a steady fuel source for the brain cells and decreases the likelihood of disruptions in energy availability. The liver produces three types of ketone bodies including b-hydroxybutyrate (BHB, measured in serum), acetoacetate (measured in urine), and acetone (measured in breath).
Ketone bodies, specifically acetoacetate and BHB, have been found to inhibit gamma-aminobutyric acid receptor-induced seizures. KDs have been found to reduce neuronal excitation and seizure activity by decreasing conversion of glutamate to asparate and potentially blocking uptake of glutamate.
Also, BHB and acetoacetate may result in membrane hyperpolarization due to increases in K(ATP) channel activity, reducing the release of neurotransmittters and inhibiting action potentials.
Ketones have also been found to reduce reactive oxygen species and inflammation that results from seizure activity.
TYPES OF KDs
All KDs reduce net carbohydrate intake (total carbohydrates less dietary fiber) and increase fat intake to alter energy metabolism. Macronutrient composition of each of the KDs found to be successful in treatment of epilepsy and how they compare to the Dietary Guidelines of Americans are shown below:
Classic KD and MCT Diet
The classic KD is the most restrictive, requiring that all foods be calculated and precisely weighed on a gram scale. This offers a higher ketogenic potential and are prescribed as a ratio of grams of fat to combined grams of carbohydrate and protein, generally as 4:1 or 3:1, while MAD, LGIT, and MCT are typically 2:1 or 1:1.
The MCT diet is more liberal in carbohydrates than the classic KD due to high intake of ketone-boosting MCT-rich fats making up 60% of total calories. MCTs result in higher ketogenic potential due to ease of digestion and absorption as they do not require bile salts for digestion. Use of the MCT diet is less common as it is sometimes limited by unpleasant gastrointestinal side effects. Instead, smaller amounts of MCTs are incorporated into other versions of the KD to enhance ketosis.
MAD and LGIT
Modified Atkins Diet (MAD) and low glycemic index treatment (LGIT) were developed in an effort to ease implementation and increase adherence to KDs. These diets use standard household measurements (cups, tablespoons, each) rather than gram weights. On MAD, net daily carbohydrate intake is limited to 10-15g for children and 20g for adults and adolescents. LGIT limited daily carbohydrates to 40-60g from foods with a glycemic index <50 to prevent rapid changes in blood glucose and insulin levels (nonstarchy vegetables, nuts, seeds, etc.)
Protein is not restricted on either version, however intakes above 0.8-1.2 g/kg actual or adjusted weight or above the dietary reference intake for age may impact ability to maintain ketosis.
Fat is encouraged, ideally 60-70% of total calories.
Multivitamin and mineral supplements are recommended.
Generally, efficacy is reported as > 50% improvement in seizure frequency, consistent among pharmaceutical outcome research for epilepsy. The KD and its variations may be effective for about half of those who trial it for drug-resistant epilepsy. More research is done on children rather than adults.
Dietary compliance was higher among those following MAD compared to classic KD. Generally, classic KD offers slightly higher efficacy but compliance is greater among modified KDs such as MAD and LGIT, and therefore may be a better long-term therapy option.
A KD is not appropriate for everyone, such as certain metabolic disorders.
Supplementing with a daily multivitamin and minerals is recommended to ensure micronutrient needs are met. All supplements should be in tablet or powder form when possible to minimize carbohydrate consumption. In general, medications in liquid, syrup, and elixir formulations may contain carbohydrates in the form of sugar or sugar alcohols and so may disrupt ketosis.
Initiation of classic and MCT KD therapy occurs by gradually titrating macronutrient composition during the course of 3-4 days. The two initiation methods are as follows: 1) replace one traditional meal with a ketogenic meal on day 1, increasing to full KD therapy by day 3; or 2) increase strength of the KD ratio daily as tolerated (1:1 on day 1, then 2:1 on day 2 and so on until goal ketosis is achieved). A slow KD introduction allows the GI tract to acclimate to changes in macronutrient composition and the gradual ketosis induction can be easier for the patient to tolerate.
Blood and urine ketone monitoring varies. Assessment of urinary ketones (acetoacetate) may be less accurate than serum BHB levels – no studies have been published comparing BHB to urine ketones among patients receiving ketogenic therapy. In addition, urinary ketones may be influenced by hydration status. The gold standard for home ketone monitoring is blood ketone (BHB) due to higher accuracy.
Initiation of lower-ratio classic KD therapy in the outpatient home environment follows similar principals as their higher-ratio counterparts and usually occurs during the course of several weeks. For the classic KD, the diet is started at a 1:1 ratio with increases weekly based on symptoms, tolerance, seizure control, and lab values. Patients may be prescribed individualized amounts of net carbohydrates, protein, and fat recommendations.
One value of particular concern for many starting the KD is the potential impact on lipid profiles. While fluctuations are likely to occur initially, these generally remain similar to baseline or may improve – specifically increases in HDL cholesterol and reductions in triglyceride levels.
LDL cholesterol values occasionally increase with KD therapy, although particle number and particle size is unclear. Low-carbohydrate diets for weight loss have been shown to increase LDL values due to an increase in particle size – larger LDL particles may be associated with a lower risk for atherosclerosis.
A 3-month commitment to KD therapy is requested of new patients and families in order to fine-tune. Mild side effects and tolerance concerns can occur during the first few days and weeks after initiation – fatigue, headaches, nausea, constipation, low blood sugar, or acidosis.
KD therapy is usually implemented for a minimum of 3-6 months and generally are followed for several years. Discontinuation should occur gradually, over the course of weeks or months to monitor for signs of seizures or other side effects. Patients are still encouraged to eat an overall healthy diet low in sugars and processed foods.